1. Field of the Invention
The present invention is directed to 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives that inhibit glycogen synthase kinase-3xcex2 (GSK-3xcex2) and are therefore useful in the treatment of mammals having disease states mediated by it. The present invention is also directed to pharmaceutical compositions containing these compounds, methods for preparing them, and methods for their use, in particular methods of treatment of diseases characterized by excess Th2 cytokines and/or an excess IgE production.
2. State of the Art
Glycogen synthase kinase (GSK) is a serine/threonine kinase for which two isoforms, xcex1 and xcex2, have been identified. Glycogen synthase kinase -3xcex2 (GSK-3xcex2) was originally identified as a protein kinase which phosphorylated and inactivated glycogen synthase a key enzyme regulating insulin-stimulated glycogen synthesis ((see Embi et al., Eur. J. Biochem. 107, 519-527, (1980); Rylatt et al., Eur. J. Biochem. 107, 529-537, (1980); and Vandenheede et al., J. Biol. Chem. 255, 11768-11774, (1980)). Subsequently, it was discovered that GSK-3xcex2 is inhibited upon insulin activation thereby allowing the activation of glycogen synthase. Therefore, inhibition of GSK-3xcex2 stimulates insulin-dependent processes and is useful in the treatment of type 2 diabetes which is characterized by decreased sensitivity to insulin and an increase in blood glucose level. A number of drugs such as 5-iodotubercidin(copyright), metformin(copyright), troglitazonem(copyright), have been used to treat diabetes. These drugs however have limited application because metformin(copyright) can cause hypoglycemia, troglitazonem(copyright) can cause severe hepatoxicity and 5-iodotubercidin(copyright), a GSK-3 inhibitor, inhibits other serine/threonine and tyrosine kinases.
Recently, it has been discovered that GSK-3xcex2 plays a role in pathogenesis of Alzheimer""s disease ((see Lovestone et al., Current Biology, 4, 1077-86 (1994), Brownlees et al., Neuroreport, 8, 3251-3255 (1997), Takashima et al., PNAS 95, 9637-9641 (1998), and Pei et al., J Neuropathol. Exp., 56, 70-78 (1997)) and bipolar disorder (see Chen et al., J. Neurochemistry, 72, 1327-1330 (1999)). It has also been discovered that GSK-3xcex2 is involved in blocking of early immune response gene activation via NF-AT and regulation of apoptosis (see Beals et al., Science, 275, 1930-33 (1997) and Pap, M. et al. J. Biochem. 273, 19929-19932, (1998)). Recently, it has also been discovered that GSK-3xcex2 is required for the NF-xcexaB mediated survival response in the TNF-xcex1 signalling pathway involved in the proinflammatory response to infection ((Hoeflich et.al., Nature, 406, 86-90 (2000)).
Furthermore, GSK-3xcex2 is also known to regulate the degradation of a protein (xcex2-catenin) which controls the activity of TCF family of transcription factors ((see., Dale,T. C., Biochem. J. 329, 209-223 (1998); Clevers, H. and van de Wetering, M., Trends in Genetics 13, 485-489 (1997); Staal, F. J. T. et al., International Immunology 11, 317-323 (1999)). The activity of this pathway has been shown to regulate the proliferation of colonic epithelial cells; and the biochemical data and clinical genetics demonstrate that it regulates the development of colon cancer.
Accordingly, there is a need for compounds that would inhibit GSK-3xcex2 and thereby provide a means for combating diseases mediated by it. This invention fulfills this and related needs.
The present invention is directed to 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives that inhibit GSK-3xcex2 and are therefore useful in the treatment of mammals having disease states mediated by it such as diabetes, Alzheimer""s disease, bipolar disorder, ischemia, traumatic brain injury, and immunodeficiency.
In addition, Applicants have discovered that inhibition of GSK-3xcex2 activity reduces the level of CD4+ T-helper 2 cells (Th2) which produce cytokines such as IL-4, IL-5, IL-13, and promote IgE production and eosinophil differentiation. This is an important discovery because it has been established that Th2 specific cytokines play a key role in the pathogenesis of diseases such as allergies and asthma. Therefore, the compounds of the present invention also provide a novel approach for the treatment of allergies and asthma.
Accordingly, in a first aspect, this invention is directed to 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives represented by Formula (I): 
wherein:
R1 and R2 independently represent hydrogen, alkyl, halo, haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino, monoalkylamino, or dialkylamino;
R3 represents hydrogen, alkyl, cycloalkyl, heteroalkyl, xe2x80x94COR7 (wherein R7 is hydrogen or alkyl), or phenyl optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino, monoalkylamino, and dialkylamino;
R4 and R5 independently represent hydrogen, alkyl, halo, haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino, monoalkylamino, or dialkylamino;
R6 is heteroalkyl, heterocyclyl, heterocyclylalkyl, heteroalkylsubstituted heterocyclyl, heteroalkylsubstituted cycloalkyl, hetereosubstituted cycloalkyl, xe2x80x94OR8, xe2x80x94S(O)nR8 (wherein n is 0 to 2; and R8 is heteroalkyl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl), xe2x80x94NR9R10 (wherein R9 is hydrogen or alkyl and R10 is heteroalkyl, heteroaralkyl, heterosubstituted cycloalkyl, heterocyclyl, or heterocyclylalkyl), or xe2x80x94X-(alkylene)xe2x80x94Yxe2x80x94Z (wherein X is a covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94S(O)n1xe2x80x94 where n1 is 0 to 2, and Y is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94Sxe2x80x94, and Z is heteroalkyl or SiR11R12R13 where R11, R12 and R13 are independently hydrogen or alkyl), or R6 together with R4 forms a methylenedioxy or ethylenedioxy group when they are adjacent to each other; or
a pharmaceutically acceptable salt thereof.
The compounds of the present invention exhibit surprisingly effective activity against GSK-3xcex2. It is contemplated that the improved activity is due to their enhanced bioavailability and increased metabolic stability.
In a second aspect, this invention is directed to a method of treatment of a disease in a mammal treatable by administration of a GSK-3xcex2 inhibitor which method comprises administration of a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt either alone or in combination with other pharmacologically active agents. In particular, the compounds of this invention are useful in treating respiratory diseases such as asthma.
In a third aspect, this invention is directed to pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a fourth aspect, this invention is directed to the use of compounds of Formula (I) in the preparation of medicaments for use in the treatment of diseases mediated by GSK-3xcex2.
In a fifth aspect, this invention provides processes for preparing compounds of Formula (I).